title: Model-based development of a PPARgamma agonist, rivoglitazone, to aid dose selection and optimize clinical trial designs.
abstract: A model-based approach was implemented for the development of the proliferator-activated receptor gamma (PPARgamma) agonist rivoglitazone. Population pharmacokinetic and pharmacodynamic models were developed using data collected from 2 phase I and 2 phase II studies in healthy volunteers and participants with type 2 diabetes mellitus. A 2-compartment model with first-order absorption and elimination and an absorption time lag best described rivoglitazone pharmacokinetics. Modified indirect-response models were used to characterize changes in fasting plasma glucose, HbA(1c), and hemodilution as a function of rivoglitazone plasma concentrations. In addition, differences in hemodilution among participants correlated with the incidence of edema. Current use of oral antidiabetic medication was a significant covariate for the fasting plasma glucose-HbA(1c) exposure-response model. Using a learn-and-confirm process, models developed prior to the second phase II study were able to make valid predictions for exposures and response variables in that study. In future studies, seamless designs can be supported by models such as those developed here.
authors.affiliation: Daiichi Sankyo Pharma Development, 399 Thornall St, Edison, NJ 08837, USA. Srohatagi@dsus.com
authors.forename: Shashank
authors.initials: S
authors.lastname: Rohatagi
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Carrothers
authors.forename: Jinyan
authors.initials: J
authors.lastname: Jin
authors.forename: William J
authors.initials: WJ
authors.lastname: Jusko
authors.forename: Tatiana
authors.initials: T
authors.lastname: Khariton
authors.forename: Joseph
authors.initials: J
authors.lastname: Walker
authors.forename: Kenneth
authors.initials: K
authors.lastname: Truitt
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Salazar
mesh_terms: D052242:Adiponectin / Q000097:blood; D000284:Administration, Oral; D000465:Algorithms; D001786:Blood Glucose / Q000032:analysis; D002853:Chromatography, Liquid; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D047495:PPAR gamma / Q000819:agonists*; D012107:Research Design; D053719:Tandem Mass Spectrometry; D045162:Thiazolidinediones / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D047495:PPAR gamma; D045162:Thiazolidinediones; C521549:rivoglitazone